Inflammation is a complex response to injury in which the immune system is activated and responds by attempting to nullify the noxious stimulus. In certain situations, however, an inappropriate immune response, often directed against host antigens, results in autoimmune diseases, such as rheumatoid arthritis, temporal arthritis, gout, systemic lupus erythematosis and possibly multiple sclerosis. These chronic degenerative disease states are usually treated aggressively with anti-inflammatory drugs and steroids. However, such therapy is often instituted after the inflammatory process is already well progressed. Cellular markers whose expression antedates a histologically obvious inflammatory response would thus clearly be useful in predicting relapses in autoimmune diseases and would allow the earlier initiation of anti-inflammatory therapy and attenuation of the disease process.
The search for such cellular markers began with the recognition that the vascular endothelium plays an active central role in the process of acute inflammation. Under the influence of proinflammatory cytokines such as tumor necrosis factor-.alpha. (TNF-.alpha.) and interleukin-1.beta. (IL-1.beta.), endothelial cells convert from an anticoagulant to a procoagulant phenotype, induce leukocyte adhesion and chemotaxis and secrete cytokines important for hematopoiesis, leukocyte activation, and smooth muscle cell proliferation. While TNF and IL-1 are not directly chemotactic, they induce endothelial cells to secrete chemotactic factors such as interleukin-8 (monocyte-derived neutrophil chemotactic factor) and monocyte chemoattractant protein 1. Adhesion of leukocytes to stimulated endothelium is facilitated by the cytokine mediated increased plasma membrane expression of intercellular adhesion molecule 1 and endothelial leukocyte adhesion molecule 1. The activated endothelium further contributes to establishing the inflammatory response by secreting additional IL-1 as well as interleukin-6 (IL-6), and several colony stimulating factors, which induce leukocyte activation and participate in the differentiation and proliferation T and B cells.
Recently a group of eight TNF-.alpha. induced immediate-early response genes derived from cultured human umbilical vein endothelial (HUVE) cells was cloned using differential hybridization. See Dixit, V. M. et al., J. Biol. Chem. 265:2973-2978 (1990). Of the eight gene products, two were chemotactic cytokines, interleukin-8 (IL-8) and monocyte chemoattractant protein 1, and two were adhesion molecules, endothelial leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. The gene products of the remaining four primary response genes, including the product of the gene of the present invention, had not been previously described.